Post-surgery adjuvant chemotherapy for breast cancer has effectively reduced metastatic recurrence rates1. However, a significant proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes critical for tumor response to specific chemotherapy drugs is a challenge, but necessary to improve outcomes2. Using integrated genomics, we identified a small number of over-expressed and amplified genes from chromosome 8q22 significantly associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. The association was confirmed in an analysis of multiple independent cohorts. Two of these genes, the anti-apoptotic gene YWHAZ, and LAPTM4B, a novel lysosomal gene, sensitized tumor cells to anthracyclines when either was depleted by siRNA knockdown and induced drug resistance when either was over-expressed. Over-expression of LAPTM4B resulted in sequestration of drug, delaying its appearance in the nucleus. Over-expression of these two genes was associated with poor tumor response to anthracycline treatment in a neo-adjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and over-expression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines, and are permissive for metastatic recurrence. These two genes may predict anthracycline resistance and influence selection of chemotherapy.

Amplification of chromosome 8q22, which includes the gene for lysosomal-associated transmembrane protein LAPTM4B, has been linked to de novo anthracycline resistance in primary breast cancers with poor prognosis. LAPTM4B overexpression can induce cytosolic retention of anthracyclines and to decrease drug induced DNA damage. In this study, we tested the hypothesis that LAPTM4B may contribute to tumor cell growth or survival in the absence of a chemotherapeutic exposure. In mammary cells, LAPTM4B protein was localized in lysosomes where its depletion increased membrane permeability, pH, cathepsin release and cellular apoptosis. Loss of LAPTM4B also inhibited later stages of autophagy by blocking maturation of the autophagosome, thereby rendering cells more sensitive to nutrient deprivation or hypoxia. Conversely, enforced overexpression of LAPTM4B promoted autophagic flux and cell survival during in vitro starvation and stimulated more rapid tumor growth in vivo. Together, our results indicate that LAPTM4B is required for lysosome homeostasis, acidification, and function, and that LAPTM4B renders tumor cells resistant to lysosome-mediated cell death triggered by environmental and genotoxic stresses.