Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis

BCL2 family members affect cell fate decisions in breast cancer but the role of BCL-W (BCL2L2) is unknown. We now show the integrated roles of the antiapoptotic BCL-W and BCL2 in affecting responsiveness to the antiestrogen ICI 182,780 (ICI; Fulvestrant Faslodex), using both molecular (siRNA; shRNA) and pharmacologic (YC137) approaches in three breast cancer variants; MCF-7/LCC1 (ICI sensitive), MCF-7/LCC9 (ICI resistant), and LY2 (ICI resistant). YC137 inhibits BCL-W and BCL2 and restores ICI sensitivity in resistant cells. Co-inhibition of BCL-W and BCL2 is both necessary and sufficient to restore sensitivity to ICI, and explains mechanistically the action of YC137. These data implicate functional cooperation and/or redundancy in signaling between BCL-W and BCL2, and suggest that broad BCL2 family member inhibitors will have greater therapeutic value than targeting only individual proteins. Whereas ICI sensitive MCF-7/LCC1 cells undergo increased apoptosis in response to ICI following BCL-W±BCL2 co-inhibition, the consequent resensitization of resistant MCF-7/LCC9 and LY2 cells reflects increases in autophagy (LC3 cleavage; p62/SQSTM1 expression) and necrosis but not apoptosis or cell cycle arrest. Thus, de novo sensitive cells and resensitized resistant cells die through different mechanisms. Following BCL-W+BCL2 co-inhibition, suppression of functional autophagy by 3-methyladenine or BECN1 shRNA reduces ICI-induced necrosis but restores the ability of resistant cells to die through apoptosis. These data demonstrate the plasticity of cell fate mechanisms in breast cancer cells in the context of antiestrogen responsiveness. Restoration of ICI sensitivity in resistant cells appears to occur through an increase in autophagy-associated necrosis. BCL-W, BCL2, and BECN1 integrate important functions in determining antiestrogen responsiveness, and the presence of functional autophagy may influence the balance between apoptosis and necrosis

Perceived risk of colorectal and breast cancers among women who are overweight or with obesity

Many overweight women or women with obesity do not acknowledge their high weight status and may be unaware of their elevated cancer risk. We explored the relationship between weight status and women's perceived risk of colorectal (CRC) and breast cancers, overall and by race/ethnicity, in a nationally representative sample.Data was combined from NHIS 2005, 2010, and 2015 sample adult questionnaires and cancer control supplements. The analytic sample included females aged 18 years and over without reported history of cancer diagnosis. Multivariable logistic regression was performed and adjusted estimates for perceived risk of CRC and breast cancers were examined, stratified by body mass index and race/ethnicity. Data were reported using predicted marginal risk ratio (PMR).Colorectal cancer risk perception remained lowest among Non-Hispanic (NH) Black women regardless of weight status (PMR = 0.53 obesity, 0.65 overweight, 0.55 normal) compared to NH White women after adjustment for all covariates. Hispanic women who were overweight or had obesity also saw themselves at lower risk of CRC compared to NH White women, however these findings were statistically insignificant. Breast cancer risk perception also remained low for NH Blacks and Hispanics at any weight compared with NH Whites.Greater effort is needed to develop, disseminate, and widely adopt or institutionalize multilevel weight management interventions and programs. These programs increase awareness of excess weight as a risk factor for cancer and empower women in diverse communities to achieve and maintain a healthy weight by adopting healthy behaviors related to nutrition and physical activity. Keywords: BMI, Cancer screening, Obesity, Overweight, Perceived ris

Apolipoprotein D expression does not predict breast cancer recurrence among tamoxifen-treated patients.

Apolipoprotein D (ApoD) has been proposed as a predictor of breast cancer recurrence among estrogen receptor-positive (ER+), tamoxifen-treated patients.We conducted a population-based case-control study nested in a population of 11,251 women aged 35-69 years at diagnosis with Stage I-III breast cancer between 1985 and 2001 on Denmark's Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers cases among women with ER+ disease treated with tamoxifen for at least 1 year and 300 cases in women with ER- disease never treated with tamoxifen. We matched one control subject per case and assessed ApoD expression in the tumor cell nucleus and cytoplasm using tissue microarray immunohistochemistry. We computed the odds ratio (OR) associating ApoD expression with recurrence and adjusted for potential confounding using logistic regression.Cytoplasmic ApoD expression was seen in 68% of ER+ tumors, in 66% of ER- tumors, and in 66% of controls across both groups. In women with ER+ tumors, the associations of cytoplasmic ApoD expression with recurrence (OR = 1.0; 95% CI = 0.7 to 1.4) and increasing cytoplasmic expression with recurrence (OR = 1.0; 95% CI = 0.996 to 1.003) were null, as were those for women with ER- tumors. Associations for nuclear ApoD expression and combined nuclear and cytoplasmic expression were similarly near-null.ApoD expression is likely not a predictor of recurrence in tamoxifen-treated patients.This study eliminates the previously suggested marker ApoD as a predictor of recurrence among tamoxifen-treated women

Frequency and proportion of breast cancer recurrence case patients and matched control subjects within group strata^*.

<p>Frequency and proportion of breast cancer recurrence case patients and matched control subjects within group strata^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171453#t001fn001" target="_blank">*</a>}.</p

Associations between ApoD expression and breast cancer recurrence within strata^*.

<p>Associations between ApoD expression and breast cancer recurrence within strata^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171453#t002fn001" target="_blank">*</a>}.</p